1,3‐diamine‐derived bifunctional organocatalyst prepared ... · 1,3-diamine-derived...

1,3-Diamine-Derived Bifunctional Organocatalyst Prepared fromCamphor

Sebastijan Ricko,a Jurij Svete,a Bogdan Stefane,a Andrej Perdih,b

Amalija Golobic,a Anze Meden,a and Uros Groselja,*a Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI-1000 Ljubljana, Slovenia

Fax: (+386)-1-2419-144; phone: (+ 386)-1-479-8563; e-mail: [email protected] National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia

Received: May 11, 2016; Revised: September 13, 2016; Published online: && &&, 0000

Dedicated to Professor Emeritus Miha Tisler, University of Ljubljana, on the occasion of his 90th birthday.

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600498.

Abstract: Chiral 1,2-diamines are privileged structur-al motifs in organocatalysis, whereas efficient 1,3-di-ACHTUNGTRENNUNGamine-derived organocatalysts are very rare. Hereinwe report a highly efficient camphor-1,3-diamine-de-rived squaramide organocatalyst. Its catalytic activityin Michael additions of 1,3-dicarbonyl nucleophiles

to trans-b-nitrostyrene derivatives provides excellentenantioselectivities (up to >99% ee).

Keywords: camphor; 1,3-diamines; Michael addition;organocatalysis; squaramides

Introduction

Inspired by the efficiency and selectivity of enzymaticcatalysis, the design of organic molecules capable ofcatalyzing efficient and stereoselective C�C bond for-mation is a formidable challenge, which is nowadaysreceiving considerable attention.[1] One of the funda-mental enzymatic catalyst competences that is diffi-cult to mimic in synthetic systems is bifunctionality;that is, the ability of a catalyst possessing acid andbase functionality to synergistically activate both thenucleophile and the electrophile reacting partners, si-multaneously.[2–4] The advent of organocatalysis in thelast decades has provided a boost to the developmentof organocatalyzed synthetic processes for the stereo-selective formation of C�C and C�X bonds includingthe construction of useful complex organic frame-works.[5]

The possibility to sterically and/or electronicallymodulate the structure of chiral 1,2-diamines has ren-dered them privileged structural motifs in organicsynthesis. They are indispensable in stereoselectivecatalysis ranging from transition metal-catalyzed reac-tions[6,7] to organocatalysis.[2–4,7] Since the pioneeringwork of Jacobsen,[8] Schreiner,[9] and Takemoto,[10] bi-functional amine-thioureas have become one of themost versatile catalyst types in asymmetric organoca-talysis.[2,3] The scope of bifunctional organocatalysis

has then been expanded by replacing the thioureawith a squaramide moiety.[2,4] Consequently, amine-thiourea and amine-squaramide catalysts havebecome work horses of non-covalent organocatalysis.In spite of their tremendous utility, these organocata-lysts are derived from a limited range of chiral struc-tural scaffolds with the 1,2-diamine moiety asa common structural motif.[2–4,11] In contrast, efficient1,3- and 1,4-diamine-derived organocatalysts [with theexception of (BINAM)-based catalysts] are very rare.Conformationally flexible guanidine-bisthiourea orga-nocatalysts have been used in asymmetric 1,4-typeFriedel–Crafts reaction of phenols[12a] and phospha-Michael reaction of diphenyl phosphonate with nitro-olefins.[12b] Ferrocene-based[12c,d] and self-assembledproline-1,3-diamine-thiourea[12e] bifunctional organo-catalysts showed high enantioselectivity in Michaeladditions of acetylacetone and aldehydes to nitroole-fins. On the other hand, tartaric acid-based 1,4-di-ACHTUNGTRENNUNGamine-thiourea organocatalysts were not effective inthe above additions (Figure 1).[12f]

Camphor is one of nature�s privileged scaffoldsreadily available in both enantiomeric forms. It under-goes a wide variety of chemical transformations whichfunctionalize, at first glance, inactivated positions,thus enabling the preparation of structurally and func-tionally very diverse products. All of the above fea-tures make camphor a highly desirable starting mate-

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rial.[13] The first reports on the application of cam-phor-derived organocatalysts date back to 2005,[14]

while this topic has recently also been reviewed.[15]

Structurally, these organocatalysts are divided intotwo categories. The first, minor one, comprises cata-lysts with a camphor skeleton as the exclusive chiralframework with camphor-derived NHC precursorsand cyclic hydrazides as typical representatives.[14a,15,16]

The vast majority of camphor-based organocatalystsconstitute the second category of mixed bifunctionalorganocatalysts, where the camphor framework is co-valently connected through a suitable spacer to an a-amino acid, most frequently a proline derivative.[15,17]

Within our continuing study on camphor-based di-ACHTUNGTRENNUNGamines as potential organocatalyst scaffolds,[18] weherein report the synthesis of a novel type of 1,3-di-ACHTUNGTRENNUNGamine-derived bifunctional squaramide organocata-lysts prepared from camphor and their application ashighly efficient catalysts in Michael additions of 1,3-dicarbonyl nucleophiles to trans-b-nitrostyrenes.

Results and Discussion

First, non-racemic 1,3-diamines 4 and 5 were preparedin four steps from (1S)-(+)-10-camphorsulfonic acid.

Following a literature procedure, camphorsulfonicacid was transformed into 10-iodocamphor (1),[19]

which was further converted with pyrrolidine into theamino ketone 2. To the best of our knowledge, theabove transformation represents the easiest way toprepare 10-aminocamphor derivatives. Subsequentcondensation of 2 with NH2OH, and reduction ofthe so-formed oxime 3 yielded a chromatographicallyseparable mixture of the minor exo- 4 and themajor endo-1,3-diamine 5 in moderate overall yields(Scheme 1).

Next, the title organocatalysts 8–12 were preparedin 26–84% yields by condensation of diamines 4 and 5with squaramates 6a–c[4e,20] or squarate 7. To haveaccess to racemic products for HPLC analysis, a newachiral organocatalyst 13 was also prepared fromsquaramate 6a and N,N-dimethylethylenediamine (14)(Scheme 2). The structures of organocatalysts 9 and10 were confirmed by single crystal X-ray analysis(Figure 2).[21,22]

Initially, organocatalysts 8–12 (5 mol% used) weretested in the 1,4-addition reaction of acetylacetone(15) to trans-b-nitrostyrene (16a) in toluene at 25 8Cfor 24 h. The results are presented in Table 1. Com-pound 9 was quickly established as the superior orga-nocatalyst, both in terms of conversion (>99%) andenantioselectivity (>98% ee) (entries 1–5). Screeningof the above reaction in various solvents (catalyst 9,25 8C, 24 h, entries 6–16) revealed that reactions gen-erally proceeded with excellent conversions (�97%)and enantioselectivities (�95% ee), though the con-version was slower in 1,4-dioxane and MeCN (en-tries 6 and 14). Diminished enantioselectivities wereobserved in MeCN (90% ee) and MeOH (79% ee)(entries 14 and 13). Reaction in brine gave 17a in96% ee (entry 15), while the neat reaction gave 17a in93% ee (entry 16).

Figure 1. Examples of typical 1,2-diamine-thiourea organo-catalysts and efficient 1,3-diamine analogues.

Scheme 1. Synthesis of camphor-derived 1,3-diamines 4 and5.



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Toluene was chosen as the solvent to be used in fur-ther transformations. Reactions at lower temperature(0 8C and �25 8C) were even more enantioselective(>99% ee), albeit with slower conversion (entries 17and 18). The conversion was much faster at 80 8C,with only slight decrease of enantioselectivity(entry 19). Lowering the catalyst loading to 0.1 mol%slowed down the conversion substantially, while enan-tioselectivity was only slightly decreased (entry 20).[21]

Under the optimum reaction conditions (toluene,25 8C, 24 h), the Rawal�s squaramide catalyst I,[4e]

Takemoto�s thiourea catalyst II,[10a] and Rawal-type

cyclohexane-1,2-diamine-based squaramide catalystIII[5f] were all outperformed by the catalyst 9 (en-tries 21–23 vs. entry 2). Notably, the efficacy of cata-lysts I–III[21] under the above conditions was also inline with the literature data.[4e,10a,5f]

Catalyst 9 was then evaluated in the alkylation ofacetylacetone (15) with trans-b-nitrostyrenes 16b–

Scheme 2. Synthesis of squaramide organocatalysts 8–13.

Figure 2. ORTEP representation of single-crystal X-raystructure of compound 9. Ellipsoids are plotted at 30%probability level.[21,22]





s under the optimum reaction conditions (toluene,25 8C, 24 h). The results are presented in Table 2.Generally, the conversions were quantitative (�97%).A moderate slowdown was observed in the case ofelectron-donating substituents (entries 1, 3, 5, and 7)and two ortho-substituents (entry 13). Enantioselec-tivities were high (>90% ee), in most cases even ex-cellent (>98% ee). Notably, persistently high selectiv-ities were obtained using ortho-monosubstituted ni-trostyrenes (entries 3, 4, 6, 8, 11, 12, and 15). In thereactions of 15 with aliphatic 1-nitroalkenes 16r and16s, the enantioselectivities were essentially the same

as in the b-nitrostyrene series 16a–q, while the yieldswere lower (entries 17 and 18).

To further explore the scope of the studied catalyticsystem, catalyst 9 was evaluated in 1,4-addition reac-tions of nitrostyrenes 16a, 16i, 16l, and 16p with se-lected 1,3-diketones and b-keto esters 18a–h(Table 3). Once again, almost all reactions proceededwith excellent conversion, while diastereoselectivityvaried with the nucleophile applied; in most casesmixtures of diastereomers were formed. Excellentdiastereoselectivity (dr>94:6) was observed in reac-tions with ethyl 2-oxocyclopentane-1-carboxylate(18f) and its 6-membered analogue 18h (entries 9 and13), and in the reaction between a-acetylbutyrolac-tone (18g) and trans-2-bromo-b-nitrostyrene (16p)(entry 12). The ee of the products ranged from 73%to >99%, most of them being �96% ee. Also here,the presence of an ortho-substituent in nitrostyrenes16i, 16l, and 16p increased the enantioselectivity incomparison to reactions with ortho-unsubstituted ni-

Table 1. Evaluation and optimization of organocatalysts 8–12 in the Michael addition of acetyl ACHTUNGTRENNUNGacetone (15) to trans-b-nitrostyrene (16a).[a]

En-try

Cat.(mol%)

Sol-vent

t [h]/T [8C]

Conv.[%]

ee[%]

1 8 (5) toluene 24/25 84 34 (R)2 9 (5) toluene 24/25 >99 (85)[b] 98 (S)3 10 (5) toluene 24/25 53 96 (S)4 11 (5) toluene 24/25 40 90 (S)5 12 (5) toluene 24/25 81 82 (S)6 9 (5) 1,4-dioxane 24/25 57 97 (S)7 9 (5) CHCl3 24/25 >99 96 (S)8 9 (5) EtOAc 24/25 97 96 (S)9 9 (5) THF 24/25 98 98 (S)10 9 (5) CH2Cl2 24/25 >99 95 (S)11 9 (5) PhCF3 24/25 >99 98 (S)12 9 (5) AcAc 24/25 >99 96 (S)13 9 (5) MeOH 24/25 >99 79 (S)14 9 (5) MeCN 24/25 60 90 (S)15 9 (5) brine 24/25 >99 96 (S)16 9 (5) neat 24/25 >99 93 (S)17 9 (5) toluene 24/0 76 >99 (S)18 9 (5) toluene 24/�25 43 >99 (S)19 9 (5) toluene 3/80 96 94 (S)20 9 (0.1) toluene 24/80 31 93 (S)21 I[c] (5) toluene 24/25 98 96 (R)22 II[c] (5) toluene 24 >99 88 (R)23 III[c] (5) toluene 24/25 >99 88 (R)

[a] Acetylacetone (15) (0.8 mmol), trans-b-nitrostyrene (16a)(0.4 mmol), solvent (1.0 mL); conversion determined by1H NMR (CDCl3); ee determined by HPLC.[21]

[b] Isolated yield.[c] I=Rawal�s squaramide catalyst;[4e] II= Takemoto�s thio-

urea catalyst;[10a] III=Rawal-type cyclohexane-1,2-dia-mine-squaramide catalyst;[5f] the structures of I–III aregiven in the Supporting Information.

Table 2. Variation of nitroalkene 16b–s in reactions with ace-tylacetone (15).[a]

En-try

R Product Yield[%][b]

ee[%]

1 4-MeO-C6H4 (16b) 17b 86 (91) 992 3-MeO-C6H4 (16c) 17c 85 (>99) 983 2-MeO-C6H4 (16d) 17d 89 (92) >994 2,5-MeO-C6H3 (16e) 17e 86 (>99) 985 4-BnO-C6H4 (16f) 17f 62 (73) 926 2-BnO-C6H4 (16g) 17g 92 (>99) >997 3,4-BnO-C6H3 (16h) 17h 72 (80) 998 2-F-C6H4 (16i) 17i 81 (>99) 999 4-Cl-C6H4 (16j) 17j 79 (>99) >9910 3-Cl-C6H4 (16k) 17k 68 (>99) 9611 2-Cl-C6H4 (16l) 17l 76 (>99) >9912 2,4-Cl-C6H3 (16m) 17m 73 (>99) >9913 2,6-Cl-C6H3 (16n) 17n 63 (82) 9114 3-Br-C6H4 (16o) 17o 80 (>99) 9415 2-Br-C6H4 (16p) 17p 87 (>99) >9916 2-furyl (16q) 17q 54 (97) 9817 1-propyl (16r) 17r 43 (72) >9918 2-propyl (16s) 17s 9 (17) 86

[a] Acetylacetone (15) (0.8 mmol), nitroalkene 16b–s (0.4 mmol), toluene (1.0 mL); conversion determinedby 1H NMR (CDCl3); ee determined by HPLC.[21]

[b] Isolated yields; the conversions are given in the brackets.





Table 3. Variation of nucleophile 18a–h in reactions with nitrostyrenes 16a, i, l, p.[a]

[a] Nucleophile (0.8 mmol), nitrostyrene (0.4 mmol), toluene (1.0 mL); conversion and dr determined by1H NMR (CDCl3); ee determined by HPLC.[21]

[b] Isolated yields; the conversions are given in brackets.





trostyrene 16a (entries 3, 6, and 10 vs. 4, 7, 8, 11, and12).

To quickly explore the scope and limitations in or-ganic synthesis, squaramide 9 was used as catalyst infive other reactions. Notably, only preliminary reac-tions were preformed devoid of optimization of thereaction conditions. The results are presented inScheme 3. Promising results (>50% yield, >50% ee)were obtained in the 1,2-addition of 15 to isatin imine23, and C-alkylation of 3-hydroxypyrrole 30 [Eqs. (2)and (5)]. On the other hand, Michael addition of 4-hydroxycoumarin (20) to enone 21 and Friedel–Craftsaminoalkylation of 4-hydroxyindole (25) with 23 werenot enantioselective, whereas 1,4-addition of nitrome-thane (27) to chalcone (28) was enantioselectivealbeit with low conversion [Eqs. (1), (3), and (4)].[21]

The kinetic profiles of the model reaction, additionof acetylacetone (15) to trans-b-nitrostyrene (16a) inthe presence of catalyst 9, were determined by1H NMR using different concentrations of the catalyst9 and reactants 15 and 16a. Reactions were performedin a rotating NMR tube in 0.75 mL of CDCl3 at302 K. The results are shown in Figure 3. First, the re-action was carried out under standard conditions (st)using 2.67 mol% catalyst loading and two-fold excessacetylacetone (15) ([9]st =1.8 � 10�3 M, [15]st =0.14 M,and [16a]st =0.07 M) (*). The reversed stoichiometryof reactants using a two-fold excess of b-nitrostyrene(16a) (&) did not affect the reaction rate as evidencedby almost identical kinetic profiles (*, &). With stan-dard concentrations of reactants, [15]st and [16a]st, andby lowering the catalyst loading to 1.35 mol% (~) and

Scheme 3. Application of catalyst 9 in some other organic reactions.





0.67 mol% (^), the reaction became much slower (*,~, ^).[21]

Next, the dependences of the initial reaction rates(v0) of the model reaction on the concentrations ofthe catalyst and the reactants, [9], [15], and [16a]were determined by 1H NMR by monitoring forma-tion of the product 17a. The logarithmic initial reac-tion rates (ln v0) were plotted against logarithmic con-centrations (ln c) as shown in Figure 4 (Plots A–C).[21]

When catalyst loading was varied at standard concen-trations of the reactants, [15]st =0.14 M and [16a]st =0.07 M, a nice linearity between ln v0 and ln [9] wasobtained and the reaction rate showed first-order de-pendence in the concentration of catalyst 9 (Figure 4,Plot A). Using standard concentrations of the catalystand the electrophile, [9]st = 1.8 �10�3 M and [16a]st, the0.5-order dependence on the nucleophile 15 was de-termined in the concentration range [15]=0.07–0.26 M, where the reaction has non-saturation kinetics(Figure 4, Plot B). Kinetic measurements with varia-ble concentrations of the electrophile [16a]= 0.017–0.14 M and with standard concentrations [9]st and[15]st revealed the first-order dependence of the initialrate on the concentration of 16a (Figure 4, Plot C).[21]

These order dependences were in line with the recent-ly published results on the kinetics of bifunctionalsquaramide-catalyzed reactions, hence, the reactionmost probably follows a bifunctional mechanism withinvolvement of the ternary complex in the C�C bondformation as the rate-determining step.[23]

Finally, the catalytic retro-Michael reaction on theracemic product rac-17a was also tested. The meas-

urements were performed in a rotating NMR tube inCDCl3 at 302 K. The concentrations of rac-17a and 9were the same ([rac-17a]= [9]=0.018 M). The racemicproduct rac-17a underwent the reversible process af-fording acetylacetone (15) and trans-b-nitrostyrene(16a) in 8% conversion within 15 h. Consequently, theremaining Michael adduct 17a present in the reactionmixture was enantiomerically enriched (7% ee) to-wards the (R)-enantiomer meaning that the (S)-enan-tiomer was selectively subjected to the retro-Michaelprocess. According to the principle of microscopic re-versibility, these observations indicate that the stereo-determining transition states for forward and back-ward reaction are the same.[24]

Figure 3. Kinetic profiles of the reaction 15+16a!17a inCDCl3 catalyzed with 9. Standard conditions: [15]st =0.14 M,[16a]st =0.07 M, and [9]st = 1.8 �10�3

M (*). Inversed condi-tions: [16a]= 0.14 M, [15]=0.07 , [9]st (&). 1.35 mol% 9 : [9]=9 � 10�4 M, [15]st, [16a]st (~). 0.67 mol% 9 : [9]=4.5 � 10�4 M,[15]st, [16a]st (^). The relative conversion of 16a was deter-mined by integrating the vinylic signal at 7.54 ppm (d, J=13.7 Hz) and by integrating the signal of the product 17a at3.88 ppm (d, J=10.0 Hz).[21]

Figure 4. Logarithmic plots of initial reaction rates (ln v0)against concentration (ln c) of the catalyst 9 (Plot A), acetyl-ACHTUNGTRENNUNGacetone (15) (Plot B), and nitrostyrene (16a) (Plot C).[21]





To gain further insight into the mechanistic aspectsand plausible origin of the high enantioselectivity ofthe 1,3-diamine-derived organocatalyst 9, densityfunctional theory (DFT) calculations were performedto find the most favored transition state and to com-pare the results with our experimental data.[21] DFTcalculations were carried out for the catalyst 9 andsubstrates 15 and 16a leading to the product 17a,taking into the account that both reactants can formH-bonds with the squaramide unit of the catalyst 9.[25]

Accordingly, all possible orientations leading to the(R)- and the (S)-isomer were considered and investi-gated.[21] Figure 5 shows the four transition state struc-tures, (S)-TS1, (R)-TS1, (S)-TS2, and (R)-TS2 thatwere allocated during the extensive computationalscan of the conformational space available to thesetransition states.

The first pair of transition state structures, (S)-TS1and (R)-TS1, corresponds to the Takemoto model:[10b]

nitrostyrene 16a is docked via H-bonds to the squara-mide unit of the catalyst 9, whereas the enolate formof the nucleophile 15 is H-bonded to the protonatedpyrrolidine part of the catalyst 9. The second pair oftransition state structures, (S)-TS2 and (R)-TS2, fol-lows the P�pai–So�s model[26] with enolate 15 H-

bonded to the squaramide unit of 9 and nitrostyrene(16a) H-bonded to the protonated pyrrolidine residueof the catalyst 9. Within the four proposed transitionstates, the (S)-TS1 is energetically most favorable.This might be explained by the almost staggeredalignment of reactants and a short distance (~0.3 nm)between the pyrrolidine�s H–N+ and the oxygen atomof the nitro group both stabilizing (S)-TS1 by dipole-dipole interactions (Figure 5).[21] Formation of the (S)-isomer of 17a via energetically most favorable transi-tion state (S)-TS1 suggests that the reaction proceedsthrough TS1 following Takemoto�s pathway.[10b] Thisis somewhat surprising, since the alternative P�pai–So�s pathway[26] through TS2 seems to be dominantfor 1,2-diamino catalysis.[25,26] The most favorabletransition state (S)-TS1 deriving the (S)-isomer of 17ais in complete agreement with the experimental ob-servations. The corresponding transition state (R)-TS1 leading to the (R)-isomer is 3.97 kcal mol�1

higher in energy that corresponds to >99% ee of the(S)-isomer selectivity. Transition states (S)-TS2 and(R)-TS2 are 7.86 and 3.78 kcal mol�1 higher in energy,respectively.[21] The observed theoretical data are inline with the results reported by P�pai and So�set al.[25,26] on a similar catalytic system and support anidea that application of a single reactivity modelmight not be generalized sufficiently for the realiza-tion of the stereoselectivity outcome of Michael addi-tions catalyzed by squaramide-derived organocata-lysts.

Conclusions

A new class of chiral squaramide catalysts based ona camphor-derived 1,3-diamine scaffold was devel-oped. Organocatalysts 8–12 are easily available from(1S)-(+)-10-camphorsulfonic acid. Catalyst 9 showsexcellent conversions and enantioselectivities (up to>99%) in 1,4-additions of 1,3-dicarbonyls to trans-b-nitrostyrene acceptors. It is distinguished by its toler-ance towards moisture and air. The kinetic measure-ments were in agreement with known results on thekinetics of the bifunctional squaramide-catalyzed re-actions, thus supporting a bifunctional reaction mech-anism.[23] DFT calculations performed on the M06-2X/6-311+ + G(d,p) level of theory fully corroboratethe experimentally observed (S)-stereoselectivity ofthe catalyst 9. The DFT calculation also suggests thatthe reaction goes by the Takemoto pathway[10b]

through (S)-TS1. Accordingly, this is the very firsttime when the original mechanistic proposal seems tobe working. The preliminary testing of catalyst 9 insome other reactions also showed promising activities,thus indicating the potential of this class of 1,3-di-ACHTUNGTRENNUNGamine building blocks for the development of new(organo)catalysts. The synthetic method allows for

Figure 5. Diagram presentations of the structures of the op-timized transition states (S)-TS1, (R)-TS1, (S)-TS2, and (R)-TS2 for the reaction 15+16 a!17 a in the presence of thecatalyst 9. The DDG values are given for the reaction in tol-uene.





easy diversification of the core scaffold by attachmentof different primary and tertiary amino residues atpositions 10 and 2 with endo- and exo-configuration.Studies on optimization of the synthesis, preparationof novel camphor-1,3-diamine based organocatalysts,and their application in different asymmetric transfor-mations, i.e. , 30!31 are underway and will be report-ed it a subsequent communication.

Experimental Section

General

Solvents for extractions and chromatography were of techni-cal grade and were distilled prior to use. Extracts were driedover technical grade Na2SO4. Melting points were deter-mined on a Kçfler micro hot stage and on SRS OptiMeltMPA100 – Automated Melting Point System (Stanford Re-search Systems, Sunnyvale, California, USA). The NMRspectra were obtained on a Bruker Avance DPX 300 at300 MHz for 1H and 75.5 MHz for 13C nucleus, and ona Bruker UltraShield 500 plus (Bruker, Billerica, Massachu-setts, USA) at 500 MHz for 1H and 126 MHz for 13C nucleus,using DMSO-d6 and CDCl3 with TMS as the internal stan-dard, as solvents. Mass spectra were recorded on an Agilent6224 Accurate Mass TOF LC/MS (Agilent Technologies,Santa Clara, California, USA), IR spectra on a Perkin–Elmer Spectrum BX FTIR spectrophotometer (Perkin–Elmer, Waltham, Massachusetts, USA). Microanalyses wereperformed on a Perkin–Elmer CHN Analyzer 2400 II (Per-kinElmer, Waltham, Massachusetts, USA). Column chroma-tography (CC) was performed on silica gel [Silica gel 60,particle size: 0.035–0.070 mm (Sigma–Aldrich, St. Louis,Missouri, USA)]. HPLC analyses were performed on anAgilent 1260 Infinity LC (Agilent Technologies, SantaClara, California, USA) using CHIRALPAK AD-H(0.46 cm ø� 25 cm) and CHIRALCEL OD-H (0.46 cm ø�25 cm) chiral columns (Chiral Technologies, Inc., WestChester, Pennsylvania, USA). Organocatalyzed reactionswere performed on EasyMax 102 Advanced synthesis work-station (Mettler-Toledo, LLC).

All the chemicals used are commercially available andwere purchased from Sigma–Aldrich (St. Louis, Missouri,USA). The source of chirality: (1S)-(+)-10-camphorsulfonicacid (1), product number C2107 Aldrich, assay: �99.0%,[a]20

D : +19.98 (c= 5 in H2O), mp 196–200 8C (dec.).

Synthesis of Organocatalyst 9

To a solution of endo-1,3-diamine 5 (4.542 mmol, 1.01 g) inanhydrous MeOH (25 mL) under argon squaramide 6a(4.954 mmol, 1.75 g) was added and the reaction mixturewas stirred at room temperature for 48 h. The resulting pre-cipitate was collected by filtration and washed with cooledEt2O (0 8C, 2 �20 mL) to give product 9 as a white solid;yield: 2.068 g (3.805 mmol, 84%); mp 226–229 8C. [a]r:t:

D :�37.9 (c=0.34, CH2Cl2:MeOH= 1:1). Anal.: C27H31F6N3O2

requires: C 59.66, H 5.75, N 7.73; found: C 59.74, H 5.52, N7.68%; EI-HR-MS: m/z= 544.2393 (MH+); C27H32F6N3O2

requires: 544.2393 (MH+); IR: nmax =3306, 3215, 2956, 2875,2800, 1801, 1657, 1539, 1489, 1457, 1417, 1381, 1343, 1301,

1276, 1170, 1129, 1001, 952, 896, 871, 843, 822, 731, 722, 707,681, 617 cm�1. 1H NMR (500 MHz, DMSO-d6): d=0.85 (s,3 H, Me), 0.90 (s, 3 H, Me), 0.87–0.99 (m, 1 H), 1.08–1.32 (m,5 H), 1.37–1.48 (m, 1 H), 1.57 (t, J=4.4 Hz, 1 H), 1.73–1.83(m, 1 H), 1.85–1.95 (m, 1 H), 2.00 (d, J= 12.6 Hz, 1 H), 2.05–2.15 (m, 2 H), 2.18–2.28 (m, 2 H), 2.28–2.39 (m, 1 H), 2.73 (d,J=12.5 Hz, 1 H), 4.57–4.67 (m, 1 H), 4.84 (dd, J= 15.3,5.8 Hz, 1 H), 4.93 (dd, J=15.0, 7.2 Hz, 1 H), 7.41 (d, J=10.2 Hz, 1 H, NH), 7.58 (s, 1 H, NH), 8.06 (s, 1 H, 1 H ofArl), 8.11 (s, 2 H, 2 H of Arl); 13C NMR (126 MHz, DMSO-d6): d= 18.8, 20.1, 23.0, 25.4, 28.4, 37.5, 44.0, 45.5, 48.9, 51.9,54.9, 57.0, 57.4, 121.2, 123.3 (q, J=272.8 Hz), 128.8 (d, J=4.0 Hz), 130.48 (q, J= 32.7 Hz), 143.0, 165.5, 169.5, 182.3,182.9.

General Procedure for the OrganocatalyzedAsymmetric Michael Addition of 1,3-DicarbonylNucleophiles to Nitroalkene Acceptors

To a solution/suspension of nitroalkene acceptor (0.4 mmol)and the tested organocatalyst 8–12 (0.1–5 mmol%) in anhy-drous solvent (1 mL) under argon at the designated temper-ature (T=�25 8C to 80 8C) the 1,3-dicarbonyl nucleophilewas added (0.8 mmol) and the resulting reaction mixturewas stirred for 3–24 h. The reaction was quenched by pass-ing it as quickly as possible through a short pad of silica gel60 (length 3–4 cm, diameter= 2 cm) using a mixture ofEtOAc and petroleum ether in a ratio of 1:1 to cut off theorganocatalyst used. Volatile components were evaporatedunder vacuum. The residue was used to determine the reac-tion conversion and diastereomer ratio by means of1H NMR analysis and the enantiomer excess of the productsby means of HPLC analysis. The novel organocatalyzedproducts were isolated by column chromatography (silicagel 60, mobile phase). Fractions containing the pure productwere combined and volatile components evaporated undervacuum followed by full characterization.

General Procedure for the Preparation of RacemicMixtures

To a solution/suspension of nitroalkene acceptor (0.4 mmol)and achiral organocatalyst 13 (0.0244 mmol, 10 mg) inCH2Cl2 (2 mL) at room temperature the 1,3-dicarbonyl com-pound was added (0.8 mmol) and the resulting reaction mix-ture was stirred at room temperature for 24 h. Volatile com-ponents were evaporated under vacuum and the residue waspurified by column chromatography (Silica gel 60, mobilephase). Fractions containing the pure racemic product(s)were combined and volatile components evaporated undervacuum followed by HPLC analysis.

Acknowledgements

Financial support from the Slovenian Research Agencythrough grant P1-0179 is gratefully acknowledged.





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